Journal of Medicinal Chemistry
Article
precipitate that formed was collected by filtration, washed with ether,
and dried under high vacuum.
the receptor provides an even more restricted binding
pocket.21,23 It is therefore possible that the larger substituents,
Cl and i-Pr in this study, cannot readily fit into the agonist
conformation and are therefore predominantly antagonist in
character, whereas the smaller substituents (CH3 and F) are
easily accommodated in the agonist conformation leading to
strong binding to the agonist conformation. However, the low
efficacy of the unsubstituted parent (1d) suggests that a small
substituent is required for good binding to the agonist
conformation.
The C20-ethyl analogues 1c, 1f, 2c, and 2d were all higher
efficacy KOP receptor agonists than their C20-methyl
homologues. Clearly the ethyl group does not provide the
extra bulk around C20 that has been reported to minimize
KOP receptor efficacy13 but is more likely accessing the site
below C8 previously identified as a region associated with KOP
receptor activation.24−26
In vivo evaluation of the lead compound, 1d, confirmed a
lack of agonist activity in the hot-plate test and the acetic acid
stretch assay which is responsive to low efficacy MOP and KOP
receptor agonists. For example, buprenorphine was a fully
effective agonist in this assay. The antagonist action of 1d was
observed as soon as 30 min after administration but dissipated
by 24 h, confirming that 1d is accessing the CNS, in line with
its lower predicted log D7.4 than buprenorphine (4.39 versus
4.81) and its predicted level of brain penetration (ACD/I-lab)
sufficient for CNS activity.
The aim of generating a ligand with a buprenorphine-like
profile but having substantially lower efficacy at MOP receptor
has been achieved in part in the current study. 1d is an
antagonist at MOP and KOP receptors (though it does have
some low efficacy at KOP receptors) and has good affinity,
equivalent or better than buprenorphine, for NOP receptors.
Efficacy at NOP receptors is, however, lower than displayed by
buprenorphine so that the desired profile is not fully realized.
(1′S,5α,6R,7R,14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-
methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-
1′-phenylethan-1′-ol (1d). N-CPM dihydronorthevinone 8a (220
mg, 0.52 mmol) in anhydrous toluene (5.2 mL) was treated with
phenylmagnesium bromide (1.5 mL, 1.04 mmol) at room temperature
for 22 h. Purification using column chromatography (30% EtOAc−
petroleum ether−0.5% NH3) gave thevinol 9a (R = Ph), (110 mg,
42%). Rf (30% EtOAc−petroleum ether−0.5% NH3) 0.7. δH (CDCl3)
7.50 (2H, d), 7.33 (2H, t), 7.18−7.26 (1H, m), 6.69 (1H, d), 6.52
(1H, d), 5.50 (1H, s), 4.42 (1H, s), 3.87 (3H, s), 3.61 (3H, s), 2.91
(1H, d), 2.86 (1H, d), 2.39−2.44 (1H, m), 2.11−2.55 (5H, m), 1.87−
1.99 (1H, m), 1.79−1.86 (2H, m), 1.79 (3H, s), 1.54−1.58 (1H, m),
0.77−1.07 (3H, m), 0.55−0.73 (1H, m), 0.33−0.39 (2H, m), −0.10 to
−0.03 (2H, m). δC (CDCl3) 147.46, 146.94, 141.66, 132.76, 128.98,
127.92, 126.79, 126.17, 119.18, 113.97, 97.14, 80.87, 59.54, 57.97,
56.90, 53.00, 48.57, 46.95, 43.52, 36.03, 35.70, 32.65, 30.06, 23.58,
22.72, 17.97, 9.35, 4.18, 3.32. m/z for C32H40NO4, [MH]+ calcd
502.2957. Found 502.2958. 9a (R = Ph) (103 mg, 0.21 mmol) was
treated as in procedure A to yield 1d after silica gel chromatography
(30% EtOAc−petroleum ether−0.5% NH3) (40.0 mg, 39%). Rf (30%
EtOAc−petroleum ether−0.5% NH3) 0.2. δH (CDCl3) 7.50 (2H, d),
7.32 (2H, t), 7.18−7.26 (1H, m). 6.62 (1H, d), 6.45 (1H, d), 5.58
(1H, s), 4.60 (1H, s), 4.42 (1H, s), 3.56 (3H, s), 2.89 (1H, d), 2.84
(1H, d), 2.40−2.42 (1H, m), 2.10−2.19 (5H, m), 1.90−2.08 (1H, m),
1.72−1.84 (3H, m), 1.80 (3H, s), 1.54−1.58 (1H, m), 1.02−1.10 (1H,
m), 0.89−0.94 (1H, dd), 0.69−0.76 (1H, m), 0.56−0.65 (1H, m),
0.30−0.40 (2H, m), −0.1 to 0 (2H, m); δC (CDCl3) 147.27, 132.44,
127.93, 126.83, 126.14, 119.56, 116.51, 97.39, 80.92, 59.52, 58.01,
52.91, 48.48, 47.24, 43.53, 36.10, 35.60, 32.60, 29.95, 23.59, 22.80,
17.97, 9.32, 4.15, 3.31. m/z found [MH]+ 488.2778. C31H38NO4
requires 488.2801. Anal. (C31H38ClNO4) C, H, N.
(1′S,5α,6R,7R,14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-
methoxy-17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-
1′-phenylmethanol (2a). The alcohol 14b (500 mg, 1.03 mmol)
was treated as in procedure A to yield 2a, which was purified by gravity
elution chromatography with MeOH−CH2Cl2. (1:20) (370 mg, 76%).
Rf (MeOH−CH2Cl2, 1:10) 0.48. NMR δH (CDCl3) 0.38−0.40 (2H,
m), 0.40−0.53 (2H, m), 0.64−0.66 (1H, m), 3.01 (1H, d), 3.35 (1H,
d), 3.80 (3H, s), 4.35 (1H, d), 4.65 (1H, d), 5.43 (1H, s), 5.56 (1H,
d), 6.00 (1H, d), 6.43 (1H, d), 6.55 (1H, d), 7.26−7.32 (5H, m). δC
(CDCl3) 3.52, 3.98, 9.18, 23.03, 30.38, 33.00, 42.59, 43.83, 43.92,
47.76, 54.86, 57.04, 59.85, 77.70, 84.53, 97.79, 116.26, 119.83, 124.37,
125.77, 127.70, 128.09, 128.23, 134.32, 137.54, 137.78, 141.71, 146.33.
m/z found M+ for C30H33NO4, 471.2404; calculated 471.2410. Mp
(HCl salt) 227−231 °C (dec, EtOH). Anal. (C30H34ClNO4·H2O) C,
H, N.
(1′R,5α,6R,7R, 14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-
methoxy-17-cyclopropylmethyl-6,14-ethenomorphinan-7-yl)-
1′-phenylmethanol (2b). The alcohol 12b (550 mg, 1.13 mmol)
was treated as in procedure A to yield 2b which was purified by gravity
elution chromatography with MeOH−CH2Cl2. (1:20) (470 mg, 88%).
Rf (MeOH−CH2Cl2, 1:10) 0.48. NMR δH (CDCl3) 0.01−0.08 (2H,
m), 0.45−0.49 (2H, m), 0.74−0.76 (1H, m), 1.37 (1H, dd), 3.05 (1H,
d), 3.53 (1H, d), 3.69 (3H, s), 4.62 (1H, d), 5.20 (1H, s), 5.49 (1H,
d), 5.81 (1H, d), 6.44 (1H, d), 6.58 (1H, d), 7.31−7.33 (5H, m). δC
(CDCl3) 3.34, 4.20, 9.30, 22.97, 24.99, 33.43, 43.04, 43.41, 44.01,
48.39, 52.24, 56.91, 59.85, 70.18, 80.85, 94.43, 116.41, 119.88, 125.72,
126.44, 126.84, 127.91, 128.18, 134.19, 136.89, 137.41, 143.32, 146.74.
m/z found M+ for C30H33NO4, 471.2408; calculated 471.2410). Mp
(HCl salt) 198−200 °C (dec, EtOH). Anal. (C30H34ClNO4·1.5H2O)
C, H, N, Cl.
(1′R,5α,6R,7R,14α)-1′-(4,5-Epoxy-7,8-dihydro-3-hydroxy-6-
methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-
1′-(2-pyridyl)ethan-1′-ol (6). 2-Bromopyridine (1.13 mmol) in dry
Et2O was cooled to −78 °C under a nitrogen atmosphere. n-
Butyllithium (1.13 mmol) was added dropwise and the mixture stirred
for 10 min before adding N-CPM dihydronorthevinone (8a, 1 mmol)
in dry THF. The reaction mixture was allowed to warm to room
temperature and stirred for 20 h. After completion, the reaction
EXPERIMENTAL SECTION
■
Reagents and solvents were purchased from Sigma-Aldrich or Alfa
Aesar and used as received. Buprenorphine (1b) was supplied by the
National Institute on Drug Abuse, Bethesda, MD. H and 13C NMR
1
spectra were obtained with a Bruker 400 MHz instrument (1H at 400
MHz, 13C at 100 MHz); δ in ppm, J in Hz with TMS as an internal
standard. Instrumentation was as follows: ESIMS, microTOF
(Bruker); EIMS, Fisons autosampler; microanalysis, PerkinElmer
240C analyzer. Column chromatography was performed using
RediSep prepacked columns with a Teledyne Isco CombiFlash
instrument. Ligands were tested as their hydrochloride salts, prepared
by adding 5 equiv of HCl (1 N solution in diethyl ether) to a solution
of compound in anhydrous methanol. All reactions were carried out
under an inert atmosphere of nitrogen unless otherwise indicated. All
compounds were >95% pure as determined by microanalysis. A
representative synthesis for each series is reported here.
General Procedure A: 3-O-Demethylation with Propane-
thiolate and HCl Salt Formation. A solution of the appropriate
thevinol (0.25 mmol) in anhydrous HMPA (1 mL) under an inert
atmosphere was treated with sodium hydride (21 mg, 0.875 mmol)
followed by 1-propanethiol (79 μL, 0.875 mmol). After the addition
was complete, the reaction mixture was heated to 120 °C and stirred
for 3 h. When the mixture was cooled to room temperature, NH4Cl
(sat., aq) was added and the mixture extracted with diethyl ether. The
organic extracts were washed with water (3×) and brine. The organic
phase was dried (MgSO4), filtered, and evaporated to dryness. The
residue was purified by column chromatography over silica gel. The
HCl salts were prepared by the addition of 2 M HCl in diethyl ether
(1.2 equiv) to a solution of the orvinol in diethyl ether. The white
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dx.doi.org/10.1021/jm401964y | J. Med. Chem. 2014, 57, 4049−4057